Generalized absence (GA) epilepsy is a childhood onset seizure disorder characterized behaviorally by an arrest of ongoing activity and loss of awareness, and electroencephalographically by generalized, bilaterally symmetrical low frequency (3-4 Hz), high voltage spike-wave discharges (SWDs). Recordings and stimulation in humans and in animal models of GA have implicated the reciprocally innervated thalamocortical system as the physiological generator of SWDs underlying GA. In addition, recently it has been hypothesized that the thalamocortical system is also involved in generation of rhythmic central activity underlying the expression of tremor in Parkinson's disease patients. This proposal describes a line of research designed to develop and test a novel preparation, which exhibits spontaneous and evoked thalamocortical rhythms in vitro. Using 400 micromole slices of mouse brain, cut in such a way as to maintain intact reciprocal connections between the somatosensory thalamus and cortex, the pharmacology and extracellular and intracellular neurophysiological correlates of spontaneous and evoked thalamocortical rhythms can be characterized using extra- and intracellular recording techniques. This type of in vitro preparation has the advantage of allowing. visualization of the central nervous system structures under study, and also allows rigorous pharmacological control of the extracellular environment, facilitating detailed physiological studies. In preliminary work, it was found that spontaneous and evoked rhythms occur in a large proportion of mouse thalamocortical slices, and that these rhythms are reminiscent of both naturally occurring and pathological EEG discharges recorded in vivo. In other preliminary work SWD-like rhythms were blocked by application of the specific GA anticonvulsant, ethosuximide. Additional work proposed focuses on two main issues: 1) a characterization of the neuromodulatory and anticonvulsant pharmacology of this thalamocortical rhythmicity model; and 2) a detailed physiological examination of thalamic and cortical neurons participating in ongoing thalamocortical rhythms, to examine the cellular correlates of EEG recordings, and to explore the role of thalamic, epithalamic, and cortical structures in the generation and maintenance of normal and pathological thalamocortical rhythms. Data derived from these studies could contribute significantly to our understanding of the cellular basis of normal sleep spindles, of GA epilepsy, and of rhythm generation mechanisms involved in Parkinsonian tremor, and provide new, testable hypotheses concerning the pathogenesis of these disorders.